US2021214723A1PendingUtilityA1

Materials and methods for treating cancer

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Assignee: MAYO FOUND MEDICAL EDUCATION & RESPriority: Jun 1, 2018Filed: May 31, 2019Published: Jul 15, 2021
Est. expiryJun 1, 2038(~11.8 yrs left)· nominal 20-yr term from priority
Inventors:Saad KenderianRosalie M. SternerMichelle J. CoxReona Sakemura
A61K 40/11A61K 40/4224A61K 40/4211A61K 40/31A61K 2239/31A61K 2239/38A61K 2239/48A61K 2300/00A61K 2121/00A61P 35/04C12N 5/0636C12N 2501/22A61K 2039/804C12N 2510/00C07K 16/2803C12N 9/22C12N 2310/20C07K 14/535C12N 2800/80A61P 35/02C07K 2319/30C07K 14/70578C12N 15/102C07K 14/7051C12N 15/11C07K 14/5412C12N 15/907C07K 2319/33C12N 15/90C12N 15/113C07K 14/70521A61K 35/17A61K 2039/5158
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Claims

Abstract

This document provides methods and materials involved in treating cancer. For example, chimeric antigen receptor T cells having reduced levels of GM-CSF are provided. Also provided as methods for making and using chimeric antigen receptor T cells having reduced levels of GM-CSF.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method for making a chimeric antigen receptor T cell having a reduced level of granulocyte-macrophage colony-stimulating factor (GM-CSF) polypeptides, said method comprising:
 introducing a nucleic acid construct into an ex vivo T cell, wherein said nucleic acid construct comprises: a) a nucleic acid encoding a guide RNA, wherein said guide RNA is complementary to a GM-CSF messenger RNA; b) a nucleic acid encoding a Cas nuclease, and c) a nucleic acid encoding said chimeric antigen receptor.   
     
     
         2 . The method of  claim 1 , wherein said guide RNA comprises a nucleic acid sequence set forth in SEQ ID NO:1. 
     
     
         3 . The method of any one of  claims 1 - 2 , wherein said Cas nuclease is Cas9 nuclease. 
     
     
         4 . The method of any one of  claims 1 - 3 , wherein said nucleic acid encoding said chimeric antigen receptor comprises a nucleic acid sequence set forth in SEQ ID NO:2. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein said nucleic acid construct is a viral vector. 
     
     
         6 . The method of  claim 5 , wherein said viral vector is a lentiviral vector. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein said chimeric antigen receptor targets a tumor-associated antigen. 
     
     
         8 . The method of  claim 7 , wherein said tumor-associated antigen is CD19. 
     
     
         9 . The method of any one of  claim 1 - 8 , wherein said introducing step comprises transduction. 
     
     
         10 . A method for making a chimeric antigen receptor T cell having a reduced level of granulocyte-macrophage colony-stimulating factor (GM-CSF) polypeptides, said method comprising:
 introducing a complex into an ex vivo T cell, wherein said complex comprises: a) a guide RNA, wherein said guide RNA is complementary to a GM-CSF messenger RNA; and b) a Cas nuclease; and   introducing a nucleic acid encoding said chimeric antigen receptor into said ex vivo T cell.   
     
     
         11 . The method of  claim 10 , wherein said guide RNA comprises a nucleic acid sequence set forth in SEQ ID NO:1. 
     
     
         12 . The method of any one of  claims 10 - 11 , wherein said Cas nuclease is Cas9 nuclease. 
     
     
         13 . The method of any one of  claims 10 - 12 , wherein said nucleic acid encoding said chimeric antigen receptor comprises a nucleic acid sequence set forth in SEQ ID NO:2. 
     
     
         14 . The method of any one of  claim 10 - 13 , wherein said complex is a ribonucleoprotein. 
     
     
         15 . The method of any one of  claims 10 - 14 , wherein said chimeric antigen receptor targets a tumor-associated antigen. 
     
     
         16 . The method of  claim 15 , wherein said tumor-associated antigen is CD19. 
     
     
         17 . The method of any one of  claim 10 - 16 , wherein said introducing steps comprises electroporation. 
     
     
         18 . A method for treating a mammal having cancer, wherein said method comprises administering chimeric antigen receptor T cells having a reduced level of granulocyte-macrophage colony-stimulating factor (GM-CSF) polypeptides to said mammal. 
     
     
         19 . The method of  claim 18 , wherein said mammal is a human. 
     
     
         20 . The method of any one of  claims 18 - 19 , wherein said cancer is a lymphoma. 
     
     
         21 . The method of  claim 20 , wherein said lymphoma is a diffuse large B cell lymphoma. 
     
     
         22 . The method of any one of  claims 18 - 19 , wherein said cancer is a leukemia. 
     
     
         23 . The method of  claim 22 , wherein said leukemia is an acute lymphoblastic leukemia. 
     
     
         24 . The method of any one of  claims 18 - 23 , wherein said chimeric antigen receptor targets a tumor-associated antigen. 
     
     
         25 . The method of  claim 24 , wherein said tumor-associated antigen is CD19. 
     
     
         26 . A method for making a chimeric antigen receptor T cell having a reduced level of cytokine polypeptides, said method comprising:
 introducing a nucleic acid construct into an ex vivo T cell, wherein said nucleic acid construct comprises: a) a nucleic acid encoding a guide RNA, wherein said guide RNA is complementary to a cytokine messenger RNA; b) a nucleic acid encoding a Cas nuclease, and c) a nucleic acid encoding said chimeric antigen receptor.   
     
     
         27 . The method of  claim 26 , wherein said cytokine polypeptides comprise granulocyte-macrophage colony-stimulating factor (GM-CSF) polypeptides and/or interleukin 6 (IL-6) polypeptides. 
     
     
         28 . The method of  claim 27 , wherein said cytokine polypeptides are GM-CSF polypeptides, and wherein said guide RNA comprises a nucleic acid sequence set forth in SEQ ID NO:1. 
     
     
         29 . The method of any one of  claims 26 - 28 , wherein said Cas nuclease is Cas9 nuclease. 
     
     
         30 . The method of any one of  claims 26 - 29 , wherein said nucleic acid encoding said chimeric antigen receptor comprises a nucleic acid sequence set forth in SEQ ID NO:2. 
     
     
         31 . The method of any one of  claims 26 - 30 , wherein said nucleic acid construct is a viral vector. 
     
     
         32 . The method of  claim 31 , wherein said viral vector is a lentiviral vector. 
     
     
         33 . The method of any one of  claims 26 - 32 , wherein said chimeric antigen receptor targets a tumor-associated antigen. 
     
     
         34 . The method of  claim 32 , wherein said tumor-associated antigen is CD19. 
     
     
         35 . The method of any one of  claim 26 - 33 , wherein said introducing step comprises transduction. 
     
     
         36 . A method for making a chimeric antigen receptor T cell having a reduced level of cytokine polypeptides, said method comprising:
 introducing a complex into an ex vivo T cell, wherein said complex comprises: a) a guide RNA, wherein said guide RNA is complementary to a cytokine messenger RNA; and b) a Cas nuclease; and   introducing a nucleic acid encoding said chimeric antigen receptor into said ex vivo T cell.   
     
     
         37 . The method of  claim 36 , wherein said cytokine polypeptides comprise granulocyte-macrophage colony-stimulating factor (GM-CSF) polypeptides and/or interleukin 6 (IL-6) polypeptides. 
     
     
         38 . The method of  claim 37 , wherein said cytokine polypeptides are GM-CSF polypeptides, and wherein said guide RNA comprises a nucleic acid sequence set forth in SEQ ID NO:1. 
     
     
         39 . The method of any one of  claims 36 - 38 , wherein said Cas nuclease is Cas9 nuclease. 
     
     
         40 . The method of any one of  claims 36 - 39 , wherein said nucleic acid encoding said chimeric antigen receptor comprises a nucleic acid sequence set forth in SEQ ID NO:2. 
     
     
         41 . The method of any one of  claim 36 - 40 , wherein said complex is a ribonucleoprotein. 
     
     
         42 . The method of any one of  claims 36 - 41 , wherein said chimeric antigen receptor targets a tumor-associated antigen. 
     
     
         43 . The method of  claim 42 , wherein said tumor-associated antigen is CD19. 
     
     
         44 . The method of any one of  claim 36 - 43 , wherein said introducing steps comprises electroporation. 
     
     
         45 . A method for treating a mammal having cancer, wherein said method comprises administering chimeric antigen receptor T cells having a reduced level cytokine polypeptides to said mammal. 
     
     
         46 . The method of  claim 45 , wherein said cytokine polypeptides comprise granulocyte-macrophage colony-stimulating factor (GM-CSF) polypeptides and/or interleukin 6 (IL-6) polypeptides. 
     
     
         47 . The method of  claim 46 , wherein said cytokine polypeptides are GM-CSF polypeptides, and wherein said guide RNA comprises a nucleic acid sequence set forth in SEQ ID NO:1. 
     
     
         48 . The method of any one of  claims 45 - 47 , wherein said mammal is a human. 
     
     
         49 . The method of any one of  claims 45 - 48 , wherein said cancer is a lymphoma. 
     
     
         50 . The method of  claim 49 , wherein said lymphoma is a diffuse large B cell lymphoma. 
     
     
         51 . The method of any one of  claims 45 - 48 , wherein said cancer is a leukemia. 
     
     
         52 . The method of  claim 51 , wherein said leukemia is an acute lymphoblastic leukemia. 
     
     
         53 . The method of any one of  claims 45 - 52 , wherein said chimeric antigen receptor targets a tumor-associated antigen. 
     
     
         54 . The method of  claim 53 , wherein said tumor-associated antigen is CD19. 
     
     
         55 . A method for improving T cell effector functions of a chimeric antigen receptor T cell, said method comprising:
 introducing a nucleic acid construct into an ex vivo T cell, wherein said nucleic acid construct comprises: a) a nucleic acid encoding a guide RNA, wherein said guide RNA is complementary to a GM-CSF messenger RNA; b) a nucleic acid encoding a Cas nuclease, and c) a nucleic acid encoding said chimeric antigen receptor.   
     
     
         56 . A method for improving T cell effector functions of a chimeric antigen receptor T cell, said method comprising:
 introducing a complex into an ex vivo T cell, wherein said complex comprises: a) a guide RNA, wherein said guide RNA is complementary to a GM-CSF messenger RNA; and b) a Cas nuclease; and   introducing a nucleic acid encoding said chimeric antigen receptor into said ex vivo T cell.

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